The entorhinal cortex has received increased attention because of neuropathological reports linking pathology to this region to such illnesses as Alzhiemer's disease and schizophrenia as well as neurobehavioral studies in primates suggesting a more critical role in cognitive processing than traditionally accepted. We have been investigating the role of the entorhinal cortex in information processing to understand how pathology in this region might result in cognitive defects associated with schizophrenia. One of the proposed primary deficits associated with the medial temporal pathology is a problem with temporal lobe - prefrontal cortical functional interaction. We studied the effects of combined versus separate removals of the prefrontal cortex and the medial temporal lobe including the hippocampus and the entorhinal cortex on the ability to learn the recognition memory task delayed non- matching to sample. In the absence of each region the monkey is capable, though mildly impaired, of learning the task, however, with combined removal the monkey becomes incapable of relearning the task. This is the first demonstration that functional interaction between the medial temporal lobe and the prefrontal cortex is necessary in cognitive processing in such a complex task. Neonatal limbic lesions including the hippocampus and the entorhinal cortex may result in abnormal temporal-prefrontal interaction thus we examined the performance of monkeys with neonatal limbic lesions on tasks known to be sensitive to, frontal damage, temporal lobe damage or to either frontal or temporal lobe damage. Our data suggest that the pattern and severity of cognitive impairment after neonatal limbic lesions is little different than after lesions as an adult. Thus while neonatal lesions may lead to social and emotional deficits that may be different than those after adult lesions the cognitive impairment at least as we tested seems to be very similar. The increased functional role of the entorhinal cortex has directed our study of its anatomical connections outside of the hippocampus to further understand important information processing pathways. Consistent with the neurobehavioral studies our anatomical data suggest an extensive interaction within the medial temporal lobe with efferent projections from the amygdala as well as the hippocampus to well defined subareas of the entorhinal and perirhinal cortex. Furthermore the entorhinal and perirhinal cortex have extensive projections to the medial thalamic region (e.g. anterior nuclei, medial dorsal nucleus), as well as other structures in the striatum such as the nucleus accumbens and caudate nucleus. These subcortical projections of the rhinal cortex are much more extensive than previously demonstrated and provide an extensive anatomical system by which the entorhinal cortex and the prefrontal cortex may interact. The experimental connectional studies with the monkey indicate unique connections with the different subareas of the entorhinal cortex with the medial temporal lobe structures, medial diencephalon, and striatum. Therefore we wanted to differentiate the different subareas in the human brain before any extensive neuropathological examination. Like the monkey brain there is an overall rostral to caudal organization to the different subareas with 5 major subareas which could be differentiated. The cyto-and mylo-organization is very similar to that we previously described for the monkey.